The overall goal of our research is to understand the molecular and cellular events that lead to cancer. Our lab in particular studies the actions of a family of proteins called STATs, which are transcription factors. Transcription factors are proteins that bind to DNA and regulate the expression of genes, which then go on to determine the phenotype and behavior of the cell. Originally, all genes were thought to code for proteins, but it is now clear that certain genes are not made into proteins. This type of gene, called a microRNA because of its relatively short length, was only recognized fairly recently. We now know that microRNAs act by inhibiting the conversion of protein-coding genes into proteins. Since their discovery, microRNAs have been found to play a part in all aspects of cancer development and progression. At present, very little is known about microRNA genes regulated by STATs and their relevance to cancer. Recently, we have identified a novel microRNA whose expression is controlled by STATs. Our proposed research will investigate the functional significance of STAT regulation of this microRNA as it relates to cancer. In our first set of experiments, we will initially characterize where STATs bind to the DNA relative to the microRNA. This will reveal how the microRNA is molecularly regulated. Next, we will assess if regulation of this microRNA is intact in cancer cells. Since the microRNA may have anti-cancer effects, we believe that STAT regulation of the microRNA goes awry in cancer. Lastly, we will analyze the causes for dysregulation of the microRNA, which could be genetic (a change in the DNA sequence) or epigenetic (other properties of the DNA change, making it harder to read). In our second set of experiments, we hypothesize that the microRNA helps to sensitize cancer cells to a stimulus, called TRAIL, that is capable of selectively killing cancer cells. First, we wll enhance or inhibit the activity of the microRNA and see if that increases or decreases sensitivity to TRAIL, respectively. Next, we will test if the microRNA acts by inhibiting a specific survival pathway. We believe that enforcing the activity of this pathway will rescue cells with enhanced activity of the microRNA. Lastly, we will test the involvement of specific genes in the actions of the microRNA. PUBLIC HEALTH RELEVANCE: Understanding the alterations that lead to cancer and the roles played by particular genes opens the door to new therapies that target those specific changes. These therapies are likely to be less toxic and more effective than current treatments because only cancerous cells harbor the alterations being targeted, and they are dependent on the alterations for malignancy. A second component of our work addresses the mechanisms of cancer cells' resistance to an anti-cancer agent being tested in the clinic, which may improve its efficacy and utility.